Although the widespread use of modern synthetic chemicals dates back many decades, we have a limited understanding of their potential impact on clinical diseases and public health. Two classes of modern chemicals, phthalates and bisphenol A (BPA), adversely affect development and reproductive function in experimental animals. Despite a majority of the U.S. general population being exposed to phthalates and BPA, there are very limited clinical and epidemiologic studies on their potential health risks, particularly in relation to fertility and pregnancy loss. In experimental studies, phthalates alter male reproductive tract development, decrease semen quality, and induce anovulatory infertility and pregnancy loss. BPA has been shown in experimental studies to lead to oocyte aneuploidy, pregnancy loss and adversely affect spermatogenesis. The proposed competing continuation is designed to determine the developmental and reproductive toxicity of phthalates and BPA in couples undergoing assisted reproductive technologies (ART), which can be used as a model for the assessment of the early stages of human development. The methods of gamete manipulation used in ART are now widely practiced and provide clinicians and epidemiologists with novel and unique opportunities to study infertility and early pregnancy loss. ART allows us to assess oocyte quality and fertilization rates, pre-implantation embryo development, and pre-clinical (early) pregnancy loss. These early developmental endpoints are not observable in women conceiving naturally, but are of high importance as they represent the majority of failures of pregnancy. Furthermore, experimental data show stage-specific differences in sensitivity to both phthalates and BPA, with early development endpoints being more sensitive to adverse affects than later pregnancy endpoints. The proposed study is a prospective preconception cohort study in which biological samples for phthalate and BPA exposure are collected at multiple time points, including preconception, periconception and throughout pregnancy. In addition, ovarian follicular fluid and amniotic fluid samples are collected to assess exposure in relevant target organs or in the fetal compartment, respectively. The specific aims include the determination of: 1) the relationship of urinary concentrations of BPA, mono-n-butyl (MnBP) and mono-(2-ethylhexyl) phthalate (MEHP), metabolites of di-n-butyl (DnBP) and di(2-ethylhexyl) phthalate (DEHP), respectively, with clinical measures of male fertility, including semen quality and sperm DNA damage; and 2) the relationship of pre- and periconception urinary concentrations of BPA, MnBP and MEHP with early developmental and pregnancy outcomes. Specific health endpoints of investigation include oocyte quality, fertilization rates, embryo quality, implantation failure and early pregnancy loss. Additional specific aims are to explore whether inter-individual phenotypic differences in DEHP metabolism modifies the association of urinary concentrations of MEHP with sperm DNA damage and adverse developmental and pregnancy endpoints. PUBLIC HEALTH RELEVANCE: Although the widespread use of modern synthetic chemicals dates back many decades, we have a limited understanding of their potential impact on clinical diseases and public health. Two classes of modern chemicals, phthalates and bisphenol A, adversely affect reproductive function in experimental animals. Despite a majority of the U.S. general population being exposed to phthalates and BPA, there are very limited clinical and epidemiologic studies on their potential health risks, particularly in relation to fertility and pregnancy loss. The proposed study will investigate associations of phthalates and BPA with male and female fertility and pregnancy outcomes.